Increasing numbers of US Veterans are returning from military ventures suffering from blast exposure and traumatic brain injury (TBI). There is a critical need for a greater understanding of the long term and debilitating impairments in cognition, psychological health, and sensorimotor abilities. To further complicate the injury, combat personnel exposed to repeated clast concussions could find themselves with long-term sequelae. The number of these individuals is increasing with the current war and poses a major challenge for the Department of Veterans Affairs. Evidence from athlete, civilian, and military populations suggests a possible `injury frequency effect' associated with concussion history for psychological and neurocognitive outcomes. To study the effects of how repeated blast exposure influences recovery after a subsequent impact-related TBI, established animal models combining multiple blast-induced neurotraumas and fluid percussion impact (FPI) will be used. Further, there is a dire need for treatment at multiple stages of TBI recovery. This research will also test a novel drug therapy that can reduce the persistent behavioral and neuropathological effects observed after repeated blast exposures followed by FPI-induced TBI. We have engineered a therapy that can halt neurodegeneration when administered after trauma. Hemostatic nanoparticles (hNPs) have been shown to reduce bleeding and increase survival in multiple trauma models, including blast. Our data indicates that hNPs alleviate anxiety-like behaviors following blast. The use of hNPs have advantages over traditional drug delivery as we can engineer versions to help improve drug delivery and bioavailability in the brain. We hypothesize that drug-loaded hNPs will enable more successful recovery of animals exhibiting symptoms comparable to the persistent cognitive and neuropsychiatric symptoms of TBI Veterans. We base our hypothesis on the premise that hNPs improve the blood brain barrier integrity, diminish oxidative stress and reduce neuroinflammation associated with blast TBI, which can induce long-lasting changes in brain function and produce negative behavioral outcomes. Expanding the scope of this study, we will also test these particles immediately after a subsequent FPI-induced TBI. Our objective is to develop an easily delivered, clinically translational pharmacotherapeuthic approach to simultaneously mitigate neuropathology and promote post-TBI recovery. To achieve this, we proposed to use Veteran-relevant rodent models to (1) determine the effect of delaying the systemically administered tempol hNPs or controls following repeated blast injury, (2) characterize the baseline injury levels of a Veteran-relevant complex TBI model that consists of repetitive blast exposure and delayed FPI-induced TBI (3) determine the efficacy of acute delivery of tempol hNPs or controls following FPI-induced TBI (subsequent to repeated blast exposure) to mitigate oxidative stress and gliosis and (4) determine the ability of acute delivery of tempol hNPs or controls following FPI-induced TBI (subsequent to repeated blast) to reduce chronic behavioral and neuropathological outcomes. This study will investigate the promise of hNPs for both a delayed treatment for repeated blast TBIs and an acute treatment for a subsequent FPI-induced TBI.